F. Kumara Mastrorosa

F. Kumara Mastrorosa

@fkma.bsky.social

Postdoctoral scholar in the Eichler Lab at UW Genome Sciences. Interested in Mendelian disorders, long-read sequencing and structural variations 🇮🇹 🇪🇺

40 followers60 following11 posts

F. Kumara Mastrorosa
@fkma.bsky.social

Our work on Trisomy 21 is finally out! We sequenced and assembled chr21 centromeres in individuals with Down syndrome and their parents. We showed that small centromeres are not inherently at risk; instead centromere size asymmetry in some young mothers might be a risk factor for nondisjunction!

The American Journal of Human Genetics@ajhgnews.bsky.social

🧬New from @eichlerlab.bsky.social 📄Complete chromosome 21 centromere sequencing of families with Down syndrome 🧑‍🤝‍🧑 @glennislogsdon.bsky.social @fkma.bsky.social & co

cell.comComplete chromosome 21 centromere sequencing of families with Down syndromeThis article describes the genetic and epigenetic landscapes of chromosome 21 centromeres in families with trisomy 21 and the general population. It reveals an extreme size asymmetry of the two matern...
F. Kumara Mastrorosa
@fkma.bsky.social

A recent preprint now supports our hypothesis and provides a mechanistic model on how centromere size asymmetry can impact meiosis I in mammals www.biorxiv.org/content/10.6...

biorxiv.orgFunctional consequences of centromeric satellite array asymmetry in female meiosisCentromeres are epigenetically specified chromosomal sites that support kinetochore assembly and often embedded within large satellite DNA arrays. Recent telomere to telomere genome assemblies have re...
F. Kumara Mastrorosa
@fkma.bsky.social

Do homologous and non-homologous acrocentric short arms recombine? And if they do, how frequently and why?

EichlerLab@eichlerlab.bsky.social

We assembled acrocentric short arms of 23 samples from a 4-generation pedigree, revealing unique mutational & recombination patterns from these highly repetitive regions usually excluded in genetic analysis. Preprint: www.biorxiv.org/content/10.6... @uwgenome.bsky.social @hhmi-science.bsky.social

F. Kumara Mastrorosa
@fkma.bsky.social

A deep analysis of the 22q11.2 locus in the human population and affected individuals studying the mechanisms and architectures that predispose to complex rearrangements!

EichlerLab@eichlerlab.bsky.social

www.biorxiv.org/content/10.1...

biorxiv.orgPopulation differences of chromosome 22q11.2 duplication structure predispose differentially to microdeletion and inversion.The most common genomic disorder, chromosome 22q11.2 microdeletion syndrome (22q11.2DS), is mediated by highly identical and polymorphic segmental duplications (SDs) known as low copy repeats (LCRs; regions A-D) that have been challenging to sequence and characterize. Here, we report the sequence-resolved genomic architecture of 135 chromosome 22q11.2 haplotypes from diverse 1000 Genomes Project samples. We find that more than 90% of the copy number variation is polarized to the most proximal LCR region A (LCRA) where 50 distinct structural configurations are observed (~189 kbp to ~2.15 Mbp or 11-fold length variation). A higher-order SD cassette structure of 105 kbp in length, flanked by 25 kbp long inverted repeats, drives this variation and emerged in the human-chimpanzee ancestral lineage later expanding in humans ~1.0 [0.8-1.2] million years ago. African LCRA haplotypes are significantly longer (p=0.0047) when compared to non-Africans yet are predicted to be more protected against recurrent microdeletions (p=0.00053) due to a preponderance of flanking SDs in an inverted orientation. Conversely, we identified nine distinct inversion polymorphisms, including five recurrent ~2.28 Mbp inversions extending across the critical region (LCRA-D) and four smaller inversions (two LCRA-B, one LCRC-D, and one LCRB-D); 7/9 of these events were identified in haplotypes of African and admixed American ancestry. Finally, we sequence and assemble four families and show that LCRA-D deletion breakpoints map to the 105 kbp repeat unit while inversion breakpoints associate with the 25 kbp repeats adjacent to palindromic AT-rich regions. In one family, we observe evidence of more complex unequal crossover events associated with gene conversion and multiple breakpoints. Our findings suggest that specific haplotype configurations are protective and susceptible to chromosome 22q11.2DS while recurrent large-scale inversions help to explain why this syndrome is less prevalent among individuals of African descent. ### Competing Interest Statement E.E.E. is a scientific advisory board (SAB) member of Variant Bio, Inc. D.P. and J.O.K. have previously disclosed a patent application (no. EP19169090) relevant to Strand-seq. P.M.L. is a founding shareholder of Repeat Diagnostic, Inc. and in Evident Genomics, Inc. He is listed as an inventor in US patent US-20250146052-A1. All other authors declare no competing interests.
F. Kumara Mastrorosa
@fkma.bsky.social

I am very happy to have contributed to the publication of the first high-quality, near-complete Middle Eastern genomes. These data will help population studies, disease gene discovery, and increase population representation in genomic datasets!

Nature Genetics@natgenet.nature.com

📢 ONLINE @natgenet.nature.com 📰Near-complete Middle Eastern genomes refine autozygosity and enhance disease-causing and population-specific variant discovery. By Mohammadmersad Ghorbani, Younes Mokrab and colleagues. ⬇️ www.nature.com/articles/s41...

nature.comNear-complete Middle Eastern genomes refine autozygosity and enhance disease-causing and population-specific variant discovery - Nature GeneticsGeneration and analysis of high-quality, genome assemblies from Middle Eastern trios demonstrate the utility of ancestry-matched data and assembly-based variation analysis.
F. Kumara Mastrorosa
@fkma.bsky.social

The most accurate way so far to study transmission, de novo variants, and recombination!

EichlerLab@eichlerlab.bsky.social

Our Nature paper (rdcu.be/ei1NM) deep sequencing a 4-generation, 28-member family using multiple sequencing technologies to study transmission of all classes of genetic variation is out! @uwgenome.bsky.social @hhmi.org @pacbio.bsky.social @utah.edu

rdcu.beHuman de novo mutation rates from a four-generation pedigree referenceNature - Analysis of more than 95% of each diploid human genome of a four-generation, twenty-eight-member family using five complementary short-read and long-read sequencing technologies provides a...
F. Kumara Mastrorosa
@fkma.bsky.social

We recently published CDR-Finder, a tool to study hypomethylated regions in centromeres (academic.oup.com/bioinformati...). The latest update allows to use the tool to study any region of the genome! This will be useful for neocentromeres, promoters and any methylation variable locus!

academic.oup.comIdentification and annotation of centromeric hypomethylated regions with CDR-FinderAbstractMotivation. Centromeres are chromosomal regions historically understudied with sequencing technologies due to their repetitive nature and short-rea

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